Growing evidence from clinical trials of the next-generation androgen receptor (AR) pathway inhibitors abiraterone acetate (AA) and MDV3100 suggests that both compounds are likely to transform the care of patients with castration-resistant prostate cancer (CRPC), and drug approvals are anticipated in the next 1 to 2 years. However, not all patients benefit from these drugs, and the durability of response in those who do respond can be short. We are focusing on two parallel strategies to achieve better clinical results: 1) developing more potent AR inhibitors, and 2) defining mechanisms of drug resistance that will guide the rational selection of combination therapies. During the current funding cycle of this project (formerly RP-6, 2008-2010), we discovered the novel antiandrogen A52, which has superior activity to MDV3100 in side-by-side comparison. We then advanced the compound (now called ARN-509) to a phase 1 clinical trial in patients with CRPC, in collaboration with a corporate partner (Aragon Pharmaceuticals). In other work, we discovered that PTEN loss (found in -40% of primary prostate cancers) confers resistance to both MDV3100 and ARN-509 in preclinical prostate cancer models, but that this resistance can be overcome by combination therapy with a dual P13K/mTOR inhibitor, BEZ235. In the proposed funding period we will conduct clinical trials that directly address 1) the role of PTEN loss as a biomarker of resistance, and 2) whether combined PI3K + next-generation AR inhibition is more active than next-generation AR inhibition alone. We will also conduct pilot studies to evaluate ARN-509 in presurgical (ie, noncastrate) patients with prostate cancer. Aim 1: To determine if PTEN loss confers resistance to the next-generation AR antagonist ARN-509 in an expansion cohort of patients with metastatic CRPC treated in an ongoing phase 1 clinical trial. Aim 2: To evaluate the activity of the dual PI3K/mT0R inhibitor BEZ235 in patients with CRPC, first alone, then in combination with abiraterone. Aim 3: To evaluate the effects of ARN-509 in localized, hormone-nave disease in presurgical trials